Alzheimer's disease (AD) is a devastating neurodegenerative disorder that results in loss of memory, cognitive function, eventually leading to dementia. A key neuropathological event in AD is the cerebral accumulation of an ~4 kDa peptide termed A beta, the principal component of senile plaques. Amyloid plaques are formed of aggregates of amyloid-beta-peptides, 37-43 amino-acid fragments (predominantly A beta_(40) and A beta_(42)) derived by serial proteolysis of the amyloid precursor protein (APP) via (3- and y-secretases. (3-Secretase has been identified as a novel membrane-tethered member of the aspartyl proteases, termed beta-site APP cleaving enzyme (BACE1) (Cole and Vassar 2008). APP proteolysis by (3-secretase results in the production of secreted (3APP (|3APPs) along with membrane-associated C99 APP-C-terminal fragments (APP-C99), which serve as a substrate for y-secretase resulting in the production of A beta.
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